Method and apparatus for rapid and selective transurethral tissue ablation

ABSTRACT

Catheter systems, tools and methods are disclosed for the selective and rapid application of DC voltage pulses to drive irreversible electroporation for minimally invasive transurethral prostate ablation. In one embodiment, a switch unit is used to modulate and apply voltage pulses from a cardiac defibrillator, while in another, the system controller can be configured to apply voltages to an independently selected multiplicity or subsets of electrodes. Devices are disclosed for more effective DC voltage application including the infusion of cooled fluid to elevate the irreversible electroporation threshold of urethral wall tissue and to selectively ablate regions of prostate tissue alone.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/US2015/035592 titled “METHOD AND APPARATUS FOR RAPID AND SELECTIVETRANSURETHRAL TISSUE ABLATION”, filed Jun. 12, 2015, which claims thebenefit of priority to U.S. Provisional Application Ser. No. 61/997,868,entitled “Methods and Apparatus for Rapid and Selective TransurethralTissue Ablation,” filed Jun. 12, 2014, the entire disclosures of whichare incorporated herein by reference in their entirety.

BACKGROUND

The embodiments described herein relate generally to medical devices fortherapeutic electrical energy delivery, and more particularly to thesurgical specialty of urology. Specifically, systems and methods fordelivering electrical energy in the context of ablating tissue rapidlyand selectively in minimally invasive transurethral clinical therapiesby the application of suitably timed pulsed voltages that generateirreversible electroporation of cell membranes. Such irreversibleelectroporation can possibly be generated in conjunction with theapplication of disclosed means of enhancing electroporation efficacy.

Transurethral resection of the prostate (TURP) remains the gold standardfor treating benign prostatic hypertrophy (BPH). Alternatives tosurgical resection are ablation of tissues using thermal-baseddestruction of tissue using multiple forms of energy (laser, microwave,radiofrequency ablation etc.). The most common postoperativecomplication with known transurethral procedures is urethral stricture,occurring in approximately 4.4% of patients overall. Furthermore knowntransurethral procedures indiscriminately resect or ablate urethralepithelium in the process of de-bulking the prostate tissues. Theurethral injury contributes to the recovery time and morbidity of theacute procedure.

In the past decade or two the technique of electroporation has advancedfrom the laboratory to clinical applications, while the effects of briefpulses of high voltages and large electric fields on tissue has beeninvestigated for the past forty years or more. It has been known thatthe application of brief high DC voltages to tissue, thereby generatinglocally high electric fields typically in the range of hundreds ofVolts/centimeter can disrupt cell membranes by generating pores in thecell membrane. While the precise mechanism of this electrically-drivenpore generation or electroporation is not well understood, it is thoughtthat the application of relatively large electric fields generatesinstabilities in the lipid bilayers in cell membranes, causing theoccurrence of a distribution of local gaps or pores in the membrane. Ifthe applied electric field at the membrane is larger than a thresholdvalue, the electroporation is irreversible and the pores remain open,permitting exchange of material across the membrane and leading toapoptosis or cell death. Subsequently the tissue heals in a naturalprocess.

Historically, known direct current ablation techniques were pioneered incardiovascular catheter-based ablation. More recently these techniqueshave been applied for the treatment of solid tumors with a clinical toolthat employed very short impulses. The application of known ablationtechniques to solid tumors on other applications, however, has notincluded selectively targeting tissue for irreversible electroporationablation. Specifically, tissue susceptibility to irreversible cellinjury from strong brief pulses of electricity depends on a number ofimportant variables. Factors include: cell size, geometry, andorientation within the electric field, the constitution of the cellmembrane and organelles, and local temperature. While pulsed DC voltagesare known to drive electroporation under the right circumstances, theexamples of electroporation applications in medicine and deliverymethods described in the prior art do not discuss specificity andrapidity of action.

Thus, there is a need for selective energy delivery for electroporationand its modulation in various tissue types as well as pulses that permitrapid action and completion of therapy delivery. There is also a needfor more effective generation of voltage pulses and control methods, aswell as appropriate devices or tools addressing a variety of specificclinical applications, particularly in minimally invasive applications.Such more selective and effective electroporation delivery methods canbroaden the areas of clinical application of electroporation includingtherapeutic treatment of a variety of cardiac arrhythmias, tissueablation, and transurethral applications.

SUMMARY

The embodiments described herein address the need for tools and methodsfor rapid and selective application of irreversible electroporationtherapy as well as pulse generation and methods in the context oftransurethral applications such as in the minimally invasive treatmentof benign prostate hyperplasia. In some embodiments [FILL IN]

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of an irreversible electroporationsystem that includes a DC voltage/signal generator, a controller unitthat is configurable to apply voltages to selected subsets of electrodeswith independent subset selections for anode and cathode and that isconnected to a computer, and one or more medical devices connected tothe controller.

FIG. 1B is a schematic illustration of an irreversible electroporationsystem that includes a DC voltage/signal generator and a controlleraccording to an embodiment.

FIG. 2 is a schematic illustration of a waveform generated by theirreversible electroporation system according to an embodiment, showinga balanced square wave.

FIG. 3 is a schematic illustration of a waveform generated by theirreversible electroporation system according to an embodiment, showinga balanced biphasic square wave.

FIG. 4 is a schematic illustration of a waveform generated by theirreversible electroporation system according to an embodiment, showinga progressive balanced biphasic square wave.

FIG. 5 is a schematic illustration of a distal portion of a catheteraccording to an embodiment, showing two distal electrodes and a lumenfor transfer of fluid through the catheter.

FIG. 6 is a schematic illustration of a distal portion of a catheteraccording to an embodiment in a tubular anatomy, where two electrodeswith the roles of cathode and anode are shown, along with a schematicdepiction of the electric field in the region between the electrodes.

FIG. 7 is a schematic illustration of a distal portion of a catheteraccording to an embodiment, where multiple electrodes are shown withtheir various respective roles of anodes or cathodes, along with aschematic depiction of the electric field in the regions between theelectrodes.

FIG. 8 is a schematic illustration of a distal portion of the cathetershown in FIG. 7, where multiple electrodes are shown along withsimulation results for isomagnitude contours of electric field linesaround the distal portion of the catheter.

FIG. 9 is an illustration of a catheter according to an embodiment witha series of lateral ablation electrodes, lateral ports for circulationof cooling fluid, and a distal balloon for holding the catheter distaltip firmly in the bladder.

FIG. 10 is an illustration of a cross section of the shaft of thecatheter shown in FIG. 9, with a multiplicity of lumens for circulationof cooling fluid, draining of the bladder, electrode leads, and distalballoon inflation.

FIG. 11 is a schematic depiction of electric field lines around thecross section of a catheter according to an embodiment with a series oflateral ablation electrodes.

FIG. 12 is a schematic illustration of the cross section of a catheteraccording to an embodiment with a series of lateral ablation electrodeslocated within a urethra surrounded by prostate tissue, with coolingfluid infused from lateral ports filling an annular space in theurethra.

FIG. 13 is an illustration of a system for selective prostate tissueelectroporation ablation according to an embodiment, including anablation catheter with ports for cooling fluid infused into the urethrato maintain the urethral tissue lining at a relatively low temperature,and a trans-rectal probe inserted into the rectum and placed inapposition to the prostate and incorporating means for delivery ofthermal energy to prostate tissue in order to maintain it at arelatively high temperature.

FIG. 14 is an illustration of an electroporation ablation catheteraccording to an embodiment, showing a series of lateral electrodes withports incorporated for circulation of cooling fluid, and including adistal balloon and a distal tip electrode.

FIG. 15 is an illustration of an electroporation ablation catheteraccording to an embodiment, showing a series of ring electrodes, aseries of lateral ports, and including a distal balloon and a distal tipelectrode.

FIG. 16 is an illustration of an electroporation ablation catheteraccording to an embodiment with a series of ring electrodes, lateralports for cooling fluid circulation and a distal tip electrode, showinga cut-away cross section view of the catheter shaft, and including amultiplicity of lumens for circulation of cooling fluid, draining of thebladder, electrode leads, and distal balloon inflation.

FIG. 17 is an illustration of an electroporation ablation catheteraccording to an embodiment, showing a long flexible electrode, a seriesof lateral ports, and including a distal balloon and a distal tipelectrode.

FIG. 18 is an illustration of an electroporation ablation catheteraccording to an embodiment, with a long flexible electrode, lateralports for cooling fluid circulation and a distal tip electrode, showinga cut-away cross section view of the catheter shaft, and including amultiplicity of lumens for circulation of cooling fluid, draining of thebladder, electrode leads, and distal balloon inflation.

FIG. 19 is an illustration of left and right lateral views of anelectroporation ablation catheter according to an embodiment with a longflexible electrode and a series of lateral ports.

FIG. 20 is a schematic illustration of a device and electroporationsystem according to an embodiment for transurethral ablation with adefibrillator voltage input.

FIG. 21 is a schematic illustration of a device and electroporationsystem according to an embodiment for transurethral ablation with adefibrillator voltage input and a cooled fluid pump for pumping coldfluid through the device.

DETAILED DESCRIPTION

Systems and methods for electroporation to ablate enlarged prostatetissue in a selective fashion are described herein. The embodimentsdescribed herein result in well-controlled and specific delivery ofelectroporation in an efficacious manner. Specifically, the systems andmethods described herein produced the desired results while ensuring atthe same time that delicate epithelial tissue in and around the urethralwall is not damaged.

The embodiments described herein account for the differences inirreversible ablation threshold by creating a local temperature gradientthat protects urethral epithelium (cooling it to raise the thresholdelectric field for ablation) and heating the target prostate tissue(warming it to make it more susceptible to ablation). In this manner,the targeted prostate tissue can be selectively ablated while leavingthe urethra intact and unaffected. As described above, strong exogenouselectrical fields can ablate tissue without significantly disrupting theextracellular matrix. The inflammatory response is relatively modestwhen compared to ablation from thermal injury. The proposed prostateablation system exploits the tissue-specific susceptibility differencesbetween the transitional epithelial cells of the urethra and theprostate tissue

In some embodiments, an apparatus includes an electrode controllerconfigured to be operably coupled to a voltage pulse generator and acatheter. The voltage pulse generator is configured to produce a pulsedvoltage waveform. The catheter includes a plurality of electrodes. Theelectrode controller is implemented in at least one of a memory or aprocessor, and includes a feedback module, a thermal control module anda pulse delivery module. The feedback module is configured to determinea temperature of a target tissue. The thermal control module isconfigured to produce a signal to control a cooling fluid to thecatheter based on the temperature of the target tissue. The pulsedelivery module is configured to deliver an output signal associatedwith the pulsed voltage waveform to the plurality of electrodes, and isfurther configured to shunt an excess current associated with the pulsedvoltage waveform

In some embodiments, an apparatus includes an electrode controllerconfigured to be operably coupled to a voltage pulse generator, acatheter and a heater. The voltage pulse generator is configured toproduce a pulsed voltage waveform. The catheter includes a plurality ofelectrodes. The electrode controller is implemented in at least one of amemory or a processor, and includes a thermal control module and a pulsedelivery module. The thermal control module is configured to produce afirst signal to control a cooling fluid to the catheter. The thermalcontrol module is configured to produce a second signal to control atemperature of a heater. The pulse delivery module configured to deliveran output signal associated with the pulsed voltage waveform to theplurality of electrodes. The pulse delivery module is further configuredto shunt an excess current associated with the pulsed voltage waveform.

In some embodiments, a method includes receiving, at a feedback moduleof an electrode controller, a temperature signal associated with atemperature of a urethral wall against which a medical a catheter isdisposed. The catheter includes a plurality of electrodes. A controlsignal based on the temperature signal is delivered to a cooling unit toproduce a flow of cooling fluid to the catheter. An output signalassociated with a pulsed voltage waveform is delivered to the pluralityof electrodes.

In some embodiments, a non-transitory processor readable medium storingcode representing instructions to be executed by a processor includescode to cause the processor to receive a temperature signal associatedwith a temperature of a urethral wall against which a medical a catheteris disposed. The medical catheter including a plurality of electrodes.The code further includes code to produce a control signal to a coolingunit to produce a flow of cooling fluid to the catheter. The controlsignal based on the temperature signal. The code further includes codeto deliver an output signal associated with the pulsed voltage waveformto the plurality of electrodes when the target tissue is at the targettemperature.

In some embodiments, a system includes a pulse generator unit, acontroller unit, a flexible medical device and a fluid pump. The pulsegenerator unit is configured to produce a pulsed voltage waveform. Thecontroller unit is connected to the pulse generator unit, and isconfigured to modulate pulses from the generator unit. The controllerunit includes shunt circuitry configured to shunt excess current. Thecontroller unit includes a thermal control module. The flexible medicaldevice includes a plurality of electrodes and defines a series of portsthrough which a cooling fluid can flow. The flexible medical device isconfigured to be connected to the controller unit such that a voltagesignal associated with the pulsed voltage waveform can be conveyed tothe plurality of electrodes. The fluid pump is configured to produce thecooling flow in response to a cooling signal produced by the thermalcontrol module of the controller unit. In some embodiments, the systemoptionally includes a trans-rectal probe including a probe head having aheater. The heater is configured to heat a portion of a prostate tissuein response to a cooling signal produced by the thermal control moduleof the controller unit.

In some embodiments, a system or method includes the use of temperatureto selectively ablate tissue as the threshold of irreversibleelectroporation is temperature-dependent, for example with the use ofpulses of cold fluid irrigation in the form of saline fluid. In thismanner, epithelial tissue in the region of the urethral wall can be leftintact, while at the same time the ablation is effectively applied onlyto deeper tissue structures adjacent to the urethral wall. The deliveryof cold fluid can be suitably pulsed in order to ensure that onlyepithelial tissue is cooled while deeper tissue is not substantivelycooled. Surprisingly, in some embodiments, the pulses of fluid flow caninvolve periodical infusions of warm fluid in time intervals betweenvoltage pulses. In one embodiment, the control of fluid pulse andtemperature parameters is also programmable.

In some embodiments, the temperature of the transurethral probe can bemodulated by other suitable methods such as a closed-loop coolant,thermoelectric transduction, and/or resistive heating coils. Atrans-rectal probe could be added to the apparatus to accentuate thedelivery of thermal energy (radiant heat, infrared, microwave,ultrasound etc.). Using a two-probe technique the rectal probe could bearranged as a dedicated heating probe and the intra-urethral device as adedicated cooling source.

The timing and intensity of thermal delivery are delivered in a mannerto optimize the local tissue thermal environment. The goal is tomaximally cool the tissues of the urethra and bladder that would beexposed to the ablation impulse while warming the targeted tissues ofthe prostate. The most direct way to achieve this is to start the cyclewith warm irrigation or radiant energy to allow heat transfer into thesurrounding prostate tissues followed by a short phase of cooling. Thelonger first phase would produce a relative steady state increase in theprostate tissue above the normal body temperature but not high enough tocause thermal tissue injury. The second, shorter phase delivers coolingto the local urethra and bladder in such a way as to quickly drop thelocal tissue temperature below normal body temperature. The ablationimpulse would be delivered into tissue with a thermal gradient favoringpreservation of the epithelial urethra while increasing susceptibilityof the prostate tissues.

In some embodiments, an irreversible electroporation system is disclosedthat includes a DC voltage/signal generator and a controller. Further,the controller is capable of applying control inputs with possiblyprogrammable voltage pulse parameters as well as programmable selectionof electrodes as cathodes or anodes. The generator can output waveformsthat can be selected to generate a sequence of voltage pulses in eithermonophasic or biphasic forms and with either constant or progressivelychanging amplitudes. Methods of control and DC voltage application froma generator capable of selective excitation of sets of electrodes aredisclosed.

In some embodiments, a method includes the treatment of benign prostatichyperplasia. In one embodiment, a standard defibrillator can be utilizedtogether with a switch to selectively apply a portion of the voltagepulse generated by the defibrillator unit, while excessive current isshunted away with a suitable shunt circuit.

The cooling irrigation fluid for any of the devices, systems and methodsdescribed herein can be any biocompatible fluid. In some embodiments,the current transfer properties of the fluid are of significantimportance, and thus the irrigation fluid is formulated to facilitatethe methods described herein. The irrigation used in the cooling phasecan have a high electrolyte content (normal saline for example) with thepossible inclusion of other biocompatible compounds to facilitateablation and reduce local injury.

In some embodiments, the irreversible electroporation system describedherein includes a DC voltage/signal generator and a controller unit forapplying voltage pulses to electrodes. In one embodiment, the signalgenerator is capable of being configured to apply voltages to a selectedmultiplicity or a subset of electrodes on a transurethral minimallyinvasive catheter device. The controller is additionally capable ofbeing programmable for voltage pulse parameters. In one embodiment wherethe device through which voltage pulses are applied also carries cooledfluid, the controller unit can also control fluid flow or pulse rate andfluid temperature.

The DC voltage is applied in brief pulses sufficient to causeirreversible electroporation and can be in the range of 0.5 kV to 10 kVand more preferably in the range 1 kV to 2.5 kV, so that a thresholdelectric field value in the range of 200-1000 Volts/cm is effectivelyachieved in the prostate tissue to be ablated. In one embodiment, the DCvoltage value is selected directly by a user from a suitable dial,slider, touch screen, or any other user interface. The DC voltage pulsealso results in a current flowing between the anode and cathodeelectrodes in the distal region of the catheter device that is insertedinto the patient urethra, with the current entering the prostate tissuefrom the anode(s) and returning back through the cathode electrodes. Theforward and return current paths (leads) are both inside the catheter.Areas of prostate tissue where the electric field is sufficiently largefor irreversible electroporation are ablated during the DC voltage pulseapplication.

As used in this specification, the singular forms “a,” “an” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, the term “a member” is intended to mean a singlemember or a combination of members, “a material” is intended to mean oneor more materials, “a processor” is intended to mean a single processoror multiple processors; and “memory” is intended to mean one or morememories, or a combination thereof.

As used herein, the terms “about” and “approximately” generally meanplus or minus 10% of the value stated. For example, about 0.5 wouldinclude 0.45 and 0.55, about 10 would include 9 to 11, about 1000 wouldinclude 900 to 1100.

A schematic diagram of the electroporation system according to anembodiment in one embodiment is shown in FIG. 1A. A DC voltage/signalgenerator 23 is driven by a controller unit 21 that interfaces with acomputer device 24 by means of a two-way communication link 29. Thecontroller can perform channel selection and routing functions forapplying DC voltages to appropriate electrodes that have been selectedby a user or by the computer 24, and apply the voltages via amultiplicity of leads (shown collectively as 26) to a catheter device22. The catheter device 22, and any of the catheter devices describedherein can be similar to the ablation catheters described in PCTPublication No. WO2014/025394, entitled “Catheters, Catheter Systems,and Methods for Puncturing Through a Tissue Structure,” filed on Mar.14, 2013 (“the '394 PCT Application), which is incorporated herein byreference in its entirety.

Some leads from the controller 21 could also carry control signals todrive pulsatile fluid flow through the device and/or for fluidtemperature control (not shown). The catheter device can also possiblysend back information such as temperature data from other sensors backto the controller 21 as indicated by the data stream 25, possibly onseparate leads. While the DC voltage generator 23 sends a DC voltage tothe controller 21 through leads 27, the voltage generator is driven bycontrol and timing inputs 28 from the controller unit 21. Multiple DCvoltage pulses can be applied in a pulse train to ensure that sufficienttissue ablation has occurred. Further, the user can repeat the deliveryof irreversible electroporation over several distinct pulse trains forfurther confidence.

In some embodiments, the electrode controller can include one or moremodules and can automatically control the flow of fluid through acatheter (e.g., to produce a pulsed flow or the like), control heatingof a particular portion of target tissue (e.g., the prostate), adjust acharacteristic of the voltage waveform, or the like. For example, FIG.1B shows an electroporation system according to an embodiment thatincludes an electrode controller 900 and a signal generator 925. In someembodiments, the signal generator 925 can be a cardiac defibrillatordevice. The electrode controller 900 is coupled to a computer 920 orother input/output device, and is configured to be operably coupled to amedical device 930. The medical device 930 can be one or more of thecatheters of the types shown and described herein. Further the medicaldevice 930 can be coupled to, disposed about and/or in contact with atarget tissue T. For example, in some embodiments, the medical devicecan be disposed within a urethra of a patient. In this manner, asdescribed herein, the electroporation system, including the electrodecontroller 900 and the signal generator 925, can deliver voltage pulsesto the target tissue for therapeutic purposes.

Moreover, in some embodiments, the electrode controller 900 isoptionally configured to be operably coupled to a medical device 935that is distinct from the medical device 930. For example, the electrodecontroller 900 can optionally be coupled to a trans-rectal probe thatincludes a mechanism for delivering heat to a portion of the targettissue (e.g., the prostate).

The controller 900 can include a memory 911, a processor 910, and aninput/output module (or interface) 901. The controller 900 can alsoinclude a temperature control module 902, a feedback module 905, and apulse delivery module 908. The electrode controller 900 is coupled to acomputer 920 or other input/output device via the input/output module(or interface) 901.

The processor 910 can be any processor configured to, for example, writedata into and read data from the memory 911, and execute theinstructions and/or methods stored within the memory 911. Furthermore,the processor 910 can be configured to control operation of the othermodules within the controller (e.g., the temperature control module 902,the feedback module 905, and the pulse delivery module 908).Specifically, the processor 910 can receive a signal including userinput, temperature data, distance measurements or the like and determinea set of electrodes to which voltage pulses should be applied, thedesired timing and sequence of the voltage pulses and the like. In otherembodiments, the processor 910 can be, for example, anapplication-specific integrated circuit (ASIC) or a combination ofASICs, which are designed to perform one or more specific functions. Inyet other embodiments, the microprocessor can be an analog or digitalcircuit, or a combination of multiple circuits.

The memory device 911 can be any suitable device such as, for example, aread only memory (ROM) component, a random access memory (RAM)component, electronically programmable read only memory (EPROM),erasable electronically programmable read only memory (EEPROM),registers, cache memory, and/or flash memory. Any of the modules (thetemperature control module 902, the feedback module 905, and the pulsedelivery module 908) can be implemented by the processor 910 and/orstored within the memory 911.

As shown, the electrode controller 900 operably coupled to the signalgenerator 925. In some embodiments, the signal generator can be acardiac defibrillator. The signal generator includes circuitry,components and/or code to produce a series of DC voltage pulses fordelivery to electrodes included within the medical device 930. Forexample, in some embodiments, the signal generator 925 can be configuredto produce a biphasic waveform having a pre-polarizing pulse followed bya polarizing pulse. The signal generator 925 can be any suitable signalgenerator of the types shown and described herein.

The pulse delivery module 908 of the electrode controller 900 includescircuitry, components and/or code to deliver an output signal associatedwith the pulsed voltage waveform produced by the signal generator 925.This signal (shown as signal 909) can be any signal of the types shownand described herein, and can be of a type and/or have characteristicsto be therapeutically effective. In some embodiments, the pulse deliverymodule 908 receives input from other portions of the system, and cantherefore send the signal 909 to the appropriate subset of electrodes,as described herein.

The electrode controller 900 includes the temperature control module902. The temperature control module 902 includes circuitry, componentsand/or code to produce a control signal (identified as signal 903) thatcan be delivered to the device 935 and/or a control signal (identifiedas signal 903′) that can be delivered to either a coolant supply (notshown) or to the medical device 930. In this manner, the temperaturecontrol module 902 can facilitate heating of a first portion of thetissue (e.g., via the device 935) and/or cooling of a second portion ofthe tissue T (e.g., the urethral walls).

In some embodiment, the ablation controller and signal generator can bemounted on a rolling trolley, and the user can control the device usinga touchscreen interface that is in the sterile field. The touchscreencan be for example an LCD touchscreen in a plastic housing mountable toa standard medical rail or post and can be used to select the electrodesfor ablation and to ready the device to fire. The interface can forexample be covered with a clear sterile plastic drape. In oneembodiment, the operator can select the electrodes involved in thevoltage pulse delivery. For example, in one embodiment the operator canselect electrodes from the touchscreen with appropriate graphicalbuttons. In one embodiment, the ablation pulse train can be initiated byholding down a hand-held trigger button that is in the sterile field,possibly with the pulse train parameters (such as for example individualpulse parameters, number of pulses in the pulse train) having beenprogrammed. The hand-held trigger button can be illuminated red toindicate that the device is “armed” and ready to ablate. The triggerbutton can be compatible for use in a sterile field and when attached tothe controller can be illuminated a different color, for example white.When the device is firing, the trigger button flashes in sequence withthe pulse delivery in a specific color such as red. The waveform of eachdelivered pulse is displayed on the touchscreen interface. While atouchscreen interface is one embodiment, other user interfaces can beused by a user to control the system such as for example a graphicaldisplay on a laptop or monitor display controlled by a standard computermouse or joystick.

In some embodiments, the system (generator and controller) according toan embodiment can deliver rectangular-wave pulses with a peak maximumvoltage of about 5 kV into a load with an impedance in the range of 30Ohm to 3000 Ohm for a maximum duration of 200 μs, with a 100 μs maximumduration being still more preferred. Pulses can be delivered in amultiplexed and synchronized manner to a multi-electrode catheter insidethe body with a duty cycle of up to 50% (for short bursts). The pulsescan generally be delivered in bursts, such as for example a sequence ofbetween 2 and 10 pulses interrupted by pauses of between 1 ms and 1000ms. The multiplexer controller is capable of running an automatedsequence to deliver the impulses/impulse trains (from the DC voltagesignal/impulse generator) to the tissue target within the body. Thecontroller system is capable of switching between subsets/nodes ofelectrodes located on the single use catheter.

The controllers and generators described herein can output waveformsthat can be selected to generate a sequence of voltage pulses in eithermonophasic or biphasic forms and with either constant or progressivelychanging amplitudes. FIG. 2 shows a rectangular wave pulse train wherethe pulses 101 have a uniform height or maximum voltage. FIG. 3 shows anexample of a balanced biphasic rectangular pulse train, where eachpositive voltage pulse such as 103 is immediately followed by a negativevoltage pulse such as 104 of equal amplitude and opposite sign. While inthis example the biphasic pulses are balanced with equal amplitudes ofthe positive and negative voltages, in other embodiments an unbalancedbiphasic waveform could also be used as may be convenient for a givenapplication. In some embodiments, generally biphasic voltage pulses areutilized to drive irreversible electroporation ablation in prostatetissue with the device and system of the present disclosure.

Yet another example of a waveform or pulse shape that can be generatedby the system is illustrated in FIG. 4, which shows a progressivebalanced rectangular pulse train, where each distinct biphasic pulse hasequal-amplitude positive and negative voltages, but each pulse such as107 is larger in amplitude than its immediate predecessor 106. Othervariations such as a progressive unbalanced rectangular pulse train, orindeed a wide variety of other variations of pulse amplitude withrespect to time can be conceived and implemented by those skilled in theart based on the teachings herein.

The time duration of each irreversible electroporation rectangularvoltage pulse could lie in the range from 1 nanosecond to 10milliseconds, with the range 10 microseconds to 1 millisecond being morepreferable and the range 50 microseconds to 300 microseconds being stillmore preferable. The time interval between successive pulses of a pulsetrain could be in the range of 10 microseconds to 1 millisecond, withthe range 50 microseconds to 300 microseconds being more preferable. Thenumber of pulses applied in a single pulse train (with delays betweenindividual pulses lying in the ranges just mentioned) can range from 1to 100, with the range 1 to 10 being more preferable. As described inthe foregoing, a pulse train can be driven by a user-controlled switchor button, in one embodiment preferably mounted on a hand-heldjoystick-like device. In one mode of operation a pulse train can begenerated for every push of such a control button, while in an alternatemode of operation pulse trains can be generated with a pre-determineddelay between successive pulse trains, for as long as theuser-controlled switch or button is engaged by the user.

A catheter device for distal ablation with the electroporation systemaccording to an embodiment is shown schematically in FIG. 5. Theablation catheter with shaft 162 has two electrodes disposed in thedistal section of the catheter, with a relatively proximally placedelectrode 164 of length L₁ exposed on the catheter shaft and arelatively distally placed electrode 163 of length L₂ also exposed onthe catheter shaft. The catheter shaft is made of a material with highdielectric strength such as for example a polymer comprising Teflon.Both electrodes are metallic, and in one embodiment the anode could bepoly-metallic in construction, for example comprising regions ofTitanium and regions of Platinum. The catheter has a lumen shown as 161and in one embodiment the distal tip portion 160 could have a diameterthat is smaller than that at the relatively proximal shaft section 162,so that the tip is tapered, making for easier insertion into theurethra. In one embodiment the electrode lengths L₁ and L₂ could bedifferent, while in an alternate embodiment they are closely similar inlength. The catheter is inserted via the urethra and positioned with itsdistal portion abutting prostate tissue in the region of which tissueablation is desired.

FIG. 6 schematically illustrates a catheter device with shaft 150 anddistal electrodes 151 and 152 disposed longitudinally in a urethralvessel in a prostate tissue region, with urethral walls indicated bydashed lines, with inner vessel wall 153 and outer vessel wall 154respectively. Thus the layer of tissue between lines 153 and 154 isepithelial tissue, while the tissue outside the outer vessel wall isprostate tissue in this schematic depiction. When the electrodes areactivated with a voltage applied across them, an electric field isgenerated in the region around and between the electrodes, depictedschematically by field lines 155 in FIG. 6. In some embodiments, thecatheter lumen carries a fluid flow of cooled fluid depicted by arrows157; the fluid can be for instance a saline fluid which is harmlesslydisposed of by the body. The temperature of the saline fluid can beabout 55 degrees Fahrenheit or lower.

In some embodiments, the time for which a cold temperature is maintainedat the patient contacting catheter surface is monitored and varied, sothat the cooling control is applied in time in a pulse-like format. Thisis done in order to maintain a surface layer of tissue at a suitably lowor cold temperature, while ensuring that deeper regions of tissueundergo no more than marginal cooling. For example, the thermaldiffusivity D of skin tissue is known to be in the range of 0.11 mm²/s.From standard heat diffusion theory, in a time T the depth x to which atemperature change applied at the surface is propagated is given (in twodimensions) by x˜√{square root over (2DT)}. Thus, in 20 seconds ofcooling, the depth x would be approximately 2 mm, which is about thethickness of skin tissue. In one mode of operation of the systemaccording to an embodiment, the cooling of the electrodes is performedin discrete time intervals in the range of 10 seconds to 40 seconds,followed by a pulse train application, the entire duration of the pulsetrain being in the range of less than about 8 seconds. Thus, theapplication of cooling could also be performed in pulses.

The urethral wall tissue in the region between dashed lines 153 and 154in FIG. 6 is then always at a cold temperature during voltage pulseapplication. This increases its irreversible electroporation threshold,thereby maintaining its integrity with no ablation occurring in thiszone. At the same time prostate tissue beyond the urethral wall, forexample in the region denoted 158 in FIG. 6, undergoes irreversibleelectroporation due to the sufficiently large electric fields in thisregion. The next ablation in the same tissue region is performed, ifnecessary, after another cooling pulse is applied over a discrete timeinterval, and so on. In one method according to an embodiment, a heatingpulse could follow a cooling pulse in order to ensure that thetemperature in the interior of the tissue does not fall below athreshold value. Suitably cold saline could generally be infused insmall quantities in each pulse, for example at a rate in the range of afew milliliters/second or less.

FIG. 7 schematically depicts one embodiment of the transurethralcatheter device according to an embodiment with multiple electrodes inits distal region. In this example, the catheter shaft 175 has fourelectrodes 170, 171, 172 and 173 disposed in its distal region. Withelectrode 172 chosen as anode and the other electrodes as cathodes, withan applied voltage the resulting electric field lines are indicatedschematically by 176. The resulting electric field intensity would belocally high in the approximate region schematically shown as the region177 inside the dashed-line ellipse, and this would serve as a selectedzone of ablation. It should be clear that by choosing differentelectrodes or electrode combinations as anodes or cathodes, the desiredzone of ablation can be varied. In one embodiment, as before thecatheter can have a lumen carrying a pulsed flow of cold fluid in orderto increase the electroporation threshold of the urethral wall. In thismanner, tissue outside the urethral wall can be selectively ablatedwhile leaving the urethral wall itself unaffected. In one embodiment thecatheter device can have at least one temperature sensor such as athermistor or thermocouple disposed in the distal portion of the devicefor monitoring temperature.

Isomagnitude contours for electric field lines corresponding to thecatheter described in the previous paragraph and depicted in FIG. 7 areillustrated in FIG. 8. As before, the catheter shaft 175 has fourelectrodes 170, 171, 172 and 173 disposed in its distal region. Given aset of electrode polarities and tissue/material properties, Maxwell'sequations can be solved for the electric field in the region surroundingthe catheter. Results from such a computational simulation areillustrated in FIG. 8, where corresponding contours of equal electricfield magnitude or isomagnitude contours were generated and are shown ascontours 181 and 182 in FIG. 8. It is evident that the contours bulgeoutward preferentially near the source electrode 172. In this manner thetreatment zone may be suitably tailored or customized as desired for theprocedure at hand.

FIG. 9 is an illustration of an embodiment of an electroporationablation catheter with a series of lateral ablation electrodes and adistal balloon. As shown in FIG. 9, the catheter has a through lumen 17and a distal balloon 1 that is inflated from a port 4 through which forexample a saline fluid is infused to expand the balloon. The catheterhas a series of electrodes such as 3 arrayed in lateral pairs as shownin the top and bottom representations (rotated by 90 degrees about thecatheter axis relative to each other) in FIG. 9, as well as a series oflateral ports 2 adjacent to respective electrodes. Electrodes leads 7and 8 of opposite polarities are used to apply voltages of opposingpolarities respectively on each electrode of a laterally opposingelectrode pair. Proximal port 4 is used to infuse or withdraw saline orother fluid to expand or contract the distal balloon 1, while ports 5and 6 are used for the circulation of cooling fluid (forward andbackward flows). In use, the catheter is positioned in the urethra withthe distal tip in the bladder; subsequently, the distal balloon isinflated, thereby holding the catheter in place within the urethra, withthe region of catheter shaft with electrodes abutting prostate tissue.The through lumen 17 is used to drain the bladder as needed in theprocedure. The series of electrodes on the device would be spaced with aseparation between closest edges in the approximate range 1 mm to 7 mm.The catheter diameter would be approximately in the range of 2 mm; thesmall separation (approximately the catheter diameter) between opposingelectrodes in a laterally opposed pair implies that a reduced voltagecan be used to drive electroporation. The catheter shaft is constructedof flexible material such as Teflon that also has a suitably highdielectric strength.

As shown in FIG. 10, the cross section of the shaft of the catheter withlateral electrodes and lateral ports has a multiplicity of lumens. Thecentral lumen 17 drains the bladder, while the electrode leads (ofopposing polarities) pass through lumens 10 and 11. Lumen 16 carriessaline or other fluid to inflate or deflate the distal balloon. Lumens12 and 13 carry cooling fluid in one direction (forward, for example),while lumens 14 and 15 carry cooling fluid in an opposite direction(backward, for example), thereby in effect circulating cooling fluidthrough the lateral ports and maintaining a circulating saline pool inthe urethra around the electrodes. The cooling fluid can be for examplesaline fluid at a temperature in the range between approximately 50degrees Fahrenheit and 75 degrees Fahrenheit, so that it issignificantly colder than normal body temperature. The cooling fluidreduces the temperature of the epithelial tissue of the urethral wall,correspondingly increasing the threshold electric field for irreversibleelectroporation. In this situation, the electric field generated betweenthe lateral electrodes leaves the urethral wall tissue unaffected, whilethe electric field in the region of prostate tissue can driveirreversible electroporation there.

FIG. 11 provides a schematic depiction of electric field lines aroundthe cross section of a catheter with a series of lateral ablationelectrodes. In FIG. 11, laterally opposing electrodes 3 are shown on theleft and right sides of the catheter shaft cross section, and when avoltage is applied across the lateral electrode pair, correspondingelectric field lines 20 are schematically shown in the illustration.

The geometry of the catheter disposed in the urethra is illustratedschematically in cross section in FIG. 12. The urethra has a urethralwall 32 and the ablation catheter 30 according to an embodiment isdisposed within the urethral cross section. Cooling fluid 31 circulatedthrough the catheter's lateral ports as described above serves to lowerthe temperature of the urethral wall 32 and generally forms an annularspace around the catheter. The cooling fluid is delivered in briefpulses no more than approximately between 10 seconds and 40 seconds induration, as described earlier. In this manner, while the urethral wallis rapidly cooled due to proximity with the cooling fluid during theapplication of electroporation voltage pulses, the prostate tissue 33external to the urethra and just adjacent to it is not cooled very much,and is thus susceptible to irreversible electroporation by the electricfield generated between the catheter electrodes. The delivery ofelectroporation voltage pulses is arranged to occur while the coolingfluid is in circulation to cool the urethral wall, with the delivery ofcooling fluid itself occurring in flow pulses that are of a longerduration than the electroporation voltage pulses as described in theforegoing.

In some embodiments, the prostate ablation system can further include atrans-rectal probe inserted into the rectum and placed in apposition tothe prostate, with the trans-rectal probe incorporating a means ofthermal energy delivery for example in the form of focused ultrasound,radiant heat source, infrared source, thermoelectric heating source, ormicrowave source or other such means of thermal energy delivery that areknown in the art. As shown in FIG. 13, the trans-rectal probe 508 isinserted into the rectum 507, and the probe has a probe head 510incorporating means for thermal energy delivery. The prostate 504 andthe bladder 505 are indicated in FIG. 13, and the trans-urethralablation catheter 501 is inserted into the urethra 503 by access throughthe penis 502. The ablation catheter has a distal balloon 506 that wheninflated, as shown in FIG. 13, serves to lodge the distal portion of thecatheter firmly within the bladder and thus the catheter itself firmlywithin the urethra with the ablation electrodes indicated as dots 511positioned adjacent to the prostate.

The rectal probe 508 heats the prostate tissue by a relatively modestamount to stay within a safe range, generating a temperature increasepreferably in the range of 3 to 10 degrees Fahrenheit. This thermalenergy delivery could itself be pulsed, for example in pulses lastingbetween approximately 10 seconds and 60 seconds, depending on the modeof thermal energy delivery and the associated specific details of heattransfer to tissue. For example, in the case where the thermal energy isdelivered by focused ultrasound by means of incorporating one or moreultrasound transducers and possibly ultrasound reflectors as wellthereby generating a focal spot or focal zone for ultrasound within theprostate tissue, the local tissue temperature in the focal zone can beincreased quite rapidly. The local tissue heating has the effect ofdecreasing the irreversible electroporation threshold electric field,thus making it possible to successfully ablate prostate tissue withgenerated electric fields that are not too large. In this case electricfield values in the range of a few hundred Volts/cm would suffice todrive irreversible electroporation in the desired treatment zone inprostate tissue, while at the same time the cooled urethral wall (cooledwith cooling fluid circulated through the ablation catheter) is leftintact without being ablated.

Several variations of ablation catheter design or embodiment can beconstructed as may be convenient from a manufacturing standpoint or forprocedural ease of use. In one variation illustrated in FIG. 14, twoviews of an ablation catheter with fluid ports co-located withelectrodes are shown in the top and bottom sketches (the two viewsdiffer by a 90 degree rotation about the catheter long axis). In thisconstruction, the ablation catheter has a distal electrode 1 and adistal balloon 65, as well as a series of laterally opposed pairs ofdistal electrodes 3 incorporating fluid ports 2. The series ofelectrodes on the device would be spaced with a separation betweenclosest edges in the approximate range 1 mm to 7 mm. Electrode leads 63and 64 connect to electrodes on opposite lateral sides respectively.Fluid track or tube 60 carries fluid (for example, saline) to inflate ordeflate the distal balloon 65, while fluid tubes 61 and 62 can supportcooling fluid circulation flow in opposite directions (for example,forward and backward respectively). The lateral fluid ports permit thecirculation of cooling fluid; thus cooling fluid exits the ports on oneside of the catheter (for example, the left side of the catheter as seenlooking down from the distal end) and enters the ports on the oppositeside of the catheter (for example, the right side of the catheter asseen looking down from the distal end). In this manner the annular spacebetween the catheter and the inner wall of the urethra is filled withcooling fluid along the portion of the catheter shaft with theelectrodes and fluid ports. Furthermore, the catheter can possiblyincorporate a through lumen for evacuation or draining of the bladder.

In another alternate embodiment of the ablation catheter according to anembodiment, as shown in FIG. 15, the catheter can have a distal tipelectrode and a distal balloon, as well as a series of ring electrodes 3and lateral fluid ports 2 disposed along a distal portion of thecatheter shaft. The lateral fluid ports are used for circulation ofcooling fluid, as described in the foregoing, while the ring electrodesand the tip electrode are used to generate an electric field forablation with suitable voltage pulses, as described above. The series ofelectrodes on the device would be spaced with a separation betweenclosest edges in the approximate range 1 mm to 7 mm. FIG. 16 shows acut-away view of such a catheter where fluid ports 5 are visible fromthe inside of the shaft, while the cross-section view providedillustrates a set or multiplicity of lumens. A central lumen 41 servesto drain the bladder, while lumens 43 and 46 are cooling fluidirrigation lumens carrying fluid flow in opposite directions (forexample, forward and backward respectively). Lumen 44 carries fluid toinflate or deflate the distal balloon, while lumens 42 and 45 act aspassages for electrode leads of opposite polarities respectively andpossibly also for cooling fluid irrigation/circulation.

In yet another alternate embodiment, the ablation catheter can have, asillustrated in FIG. 17, a distal tip electrode, a distal balloon, a longflexible electrode 3 (for example, in the form of a long helical windingof metallic composition) and a set of lateral ports 2 on either side ofthe catheter for circulation of cooling fluid. The series of lateralports on the device would be spaced with a separation between closestedges in the approximate range 1 mm to 7 mm. As shown in the cut-awayview of such a catheter in FIG. 18, fluid ports 3 are visible from theinside of the shaft, while the cross-section view provided illustrates aset or multiplicity of lumens. A central lumen 50 serves to drain thebladder, while lumens 52 and 54 are cooling fluid irrigation lumenscarrying fluid flow in opposite directions (for example, forward andbackward respectively). Lumen 55 carries fluid to inflate or deflate thedistal balloon, while lumens 51 and 53 act as passages for electrodeleads of opposite polarities respectively and possibly also for coolingfluid irrigation/circulation.

In still another alternate embodiment of ablation catheter shown in FIG.19, left and right views of a catheter with proximal end 71 and distalend 72 are both shown for clarity (left and right views are marked L andR respectively), the catheter having a long flexible electrode 80 andlateral ports 6 for cooling fluid irrigation through the irrigationshaft 75 with lumen 77 for fluid irrigation as well as electrode leads.The distal electrode is not marked.

In the embodiments with a distal electrode, while the distal electrodecan generally be either an anode or a cathode, in some embodiments it isa cathode, since this can reduce the likelihood of flash arcing. Thevarious embodiments of ablation catheters described above can be used inTrans-Urethral Rectoscopy Procedures (TURP), where the tissue resectionis performed by irreversible electroporation ablation. In such anapplication, as shown in FIG. 20, an ablation catheter device 401 withmultiple electrodes is shown (two electrodes 402 and 403 marked in itsdistal portion are shown for schematic illustration purposes). Thecatheter in this embodiment can be connected to a pulse generator 409 inthe form of a defibrillator unit, which could possibly be a standardcommercial unit such as a Booker Box. The catheter can incorporate anIGBT switch, possibly disposed in the catheter handle 405. In someembodiments, the switch can even be mounted in a disposable unit or box407 that connects to the catheter handle and interfaces with thedefibrillator unit. In an alternate embodiment, the switch can beincorporated in the catheter handle. The switch unit is designed tooperate in pulsed fashion so that for example only a discrete timeinterval of pulse, for example 700 microseconds of defibrillator output,is passed through the catheter in a set of discrete pulses. The switchunit also is capable of accepting a variety of DC voltage sources, andhas an in-built shunt circuit to shed or shunt away excess current. Inthis manner, even a standard defibrillator could be used with theablation catheter device described herein to generate irreversibleelectroporation. In particular, the ablation catheter device can be verybeneficial in Trans-Urethral clinical applications such as TURP.

As shown in FIG. 21, in some embodiments the catheter handle 405 canfurther be connected to a fluid pump 413 capable of pumping cooled fluidsuch as cooled saline through the catheter. Preferably the pump iscapable of delivering and controlling pulsatile fluid flow wherein thefluid is delivered in pulses. In one embodiment the saline pump candeliver either cooled or heated or warmed fluid, while in anotherembodiment the saline pump can deliver cooled fluid while a trans-rectalprobe with a means of inducing heating of prostate tissue is also usedin the procedure. As indicated by the dashed lines between switch unit407 and fluid pump 413, the switch unit can also drive control signalsto the pump for setting fluid pulse control parameters such as fluidtemperature and flow. Furthermore, when the ablation catheter is used inconjunction with a trans-rectal probe, the switch unit is capable ofsuitably timing or coordinating the delivery of cooling fluid throughthe catheter and thermal energy delivery via the rectal probe. In someembodiments the thermal energy delivery from the rectal probe is alsoperformed in pulsed fashion.

In an alternate embodiment, instead of a defibrillator unit, the signalgenerator box 409 could comprise a programmable pulse generator of thetypes previously described herein. In a further alternate embodiment,such programmability (for example, of electrode selection) can be madefrom the switch unit 407, possibly through connection to a computer orother user interface. Further, in one embodiment sensed temperature datafrom the distal portion of the medical device (from a thermistor orthermocouple, for example) can be used to adjust the temperature of thesaline fluid flow.

While various specific examples and embodiments of systems and tools forselective tissue ablation with irreversible electroporation weredescribed in the foregoing for illustrative and exemplary purposes, itshould be clear that a wide variety of variations and alternateembodiments could be conceived or constructed by those skilled in theart based on the teachings according to an embodiment. While specificmethods of control and DC voltage application from a generator capableof selective excitation of sets of electrodes were disclosed, personsskilled in the art would recognize that any of a wide variety of othercontrol or user input methods and methods of electrode subset selectionetc. can be implemented without departing from the scope according to anembodiment. Likewise, while the foregoing described a range of specifictools or devices for more effective and selective DC voltage applicationfor irreversible electroporation through fluid irrigation and catheterdevices, other device constructions or variations could be implementedby one skilled in the art by employing the principles and teachingsdisclosed herein without departing from the scope according to anembodiment in a variety of medical applications.

Furthermore, while the present disclosure describes specific embodimentsand tools involving irrigation with saline fluids and the use oftemperature to selectively ablate tissue by taking advantage of thetemperature-dependence of the threshold of irreversible electroporation,it should be clear to one skilled in the art that a variety of methodsand devices for steady or pulsed fluid delivery, or for tissue orelectrode cooling, or thermal energy delivery via a trans-rectal probe,could be implemented utilizing the methods and principles taught hereinwithout departing from the scope according to an embodiment.

Accordingly, while many variations of methods and tools disclosed herecan be constructed, the scope according to an embodiment is limited onlyby the appended claims.

The invention claimed is:
 1. An apparatus, comprising: an electrodecontroller configured to be operably coupled to a voltage pulsegenerator, a catheter and a heater, the voltage pulse generatorconfigured to produce a pulsed voltage waveform, the catheter includinga plurality of electrodes, the electrode controller implemented in atleast one of a memory or a processor, the electrode controller includinga thermal control module and a pulse delivery module, the thermalcontrol module configured to produce a first signal to control a coolingfluid to the catheter, the thermal control module configured to producea second signal to control a temperature of a heater, the pulse deliverymodule configured to deliver an output signal associated with the pulsedvoltage waveform to the plurality of electrodes, the pulse deliverymodule further configured to shunt an excess current associated with thepulsed voltage waveform.
 2. The apparatus of claim 1, wherein thevoltage pulse generator unit is a cardiac defibrillator.
 3. Theapparatus of claim 1, wherein the pulse delivery module is configured toselect at least a first electrode from the plurality of electrodes and asecond electrode from the plurality of electrodes and deliver the outputsignal associated with the pulsed voltage waveform to the firstelectrode and the second electrode.
 4. The apparatus of claim 1, whereinthe pulse delivery module is configured to modulate a characteristic ofthe output signal, the characteristic including at least one of anamplitude of the output signal, a period of the output signal, orduration of the output signal.
 5. The apparatus of claim 1, wherein thepulse delivery module is configured produce the output signal byincorporating intervals with zero voltage into voltage pulses from thevoltage pulse generator.
 6. The apparatus of claim 1, wherein theelectrode controller is configured to interface with an external deviceto program at least one of an amplitude of the output signal, a periodof the output signal, or a duration of the output signal.
 7. Theapparatus of claim 1, further comprising: the catheter, a proximal endof the catheter including a handle, at least a portion of the electrodecontroller disposed within the handle.
 8. The apparatus of claim 1,wherein the thermal control module is configured to produce the signalto control at least one of a flow of the cooling fluid or a temperatureof the cooling fluid.
 9. The apparatus of claim 1, wherein: the catheteris configured to be disposed within a urethra such that the plurality ofelectrodes can supply voltage to a prostate; and the heater is includedin a trans-rectal probe.
 10. The apparatus of claim 1, wherein theheater is an ultrasound heater, the second signal is configured tocontrol a characteristic of ultrasound energy produced by the ultrasoundheater.
 11. The apparatus of claim 1, wherein the heater is an infraredheater, the second signal is configured to control a characteristic ofinfrared energy produced by the infrared heater.
 12. The apparatus ofclaim 1, further comprising: an inflation controller configured to beoperably coupled to the catheter, the catheter including an expandablemember, the inflation controller implemented in at least one of a memoryor a processor, the inflation controller configured to produce aninflation signal to control an inflation fluid to the expandable member.13. A system, comprising: a pulse generator unit configured to produce apulsed voltage waveform; a controller unit connected to the pulsegenerator unit, the controller unit configured to modulate pulses fromthe generator unit, the controller unit including shunt circuitryconfigured to shunt excess current; the controller unit including athermal control module; a flexible medical device including a pluralityof electrodes, the flexible medical device defining a plurality of portsthrough which a cooling fluid can flow, the flexible medical deviceconfigured to be connected to the controller unit such that a voltagesignal associated with the pulsed voltage waveform can be conveyed tothe plurality of electrodes; a fluid pump configured to produce thecooling flow in response to a cooling signal produced by the thermalcontrol module of the controller unit; and a trans-rectal probeincluding a probe head having a heater, the heater configured to heat aportion of a prostate tissue in response to a cooling signal produced bythe thermal control module of the controller unit.
 14. The system ofclaim 13, wherein the heater is configured to produce a focusedultrasound energy pulse to heat the portion of the prostate tissue. 15.The system of claim 13, wherein the heater is configured to produce aninfrared energy pulse to heat the portion of the prostate tissue. 16.The system of claim 13, wherein the catheter includes an expandablemember configured to limit movement of catheter within the urethra.